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Background The Clinical Treatment Score post-5 years (CTS5) integrates four clinicopathological variables to estimate the residual disease recurrence risk in hormone receptor-positive breast cancer patients who have been treated with five years of adjuvant endocrine therapy. This study aimed to determine the accuracy of the CTS5. Methods A systematic review was performed in accordance with the PRISMA statement. Studies relevant for inclusion in the current review were identified from The Cochrane Library, EBSCO, Ovid, PubMed, and Embase. Results Six papers reported on 30 354 postmenopausal patients (age range 42 to 91 years). The pooled hazard ratio (HR) of distant recurrence relative to the low-risk CTS5 category was 5.41 (95% c.i. 4.50 to 6.51; P < 0.05) for the high-risk CTS5 category and 2.32 (95% c.i. 1.90–2.84; P < 0.05) for the intermediate CTS5 category. Three papers reported on 10 425 premenopausal patients (age range 18 to 54 years). The pooled HR of distant recurrence relative to the low-risk CTS5 category was 5.42 (95% c.i. 2.26 to 13.01; P < 0.05) for the high-risk CTS5 category and 2.82 (95% c.i. 1.35 to 5.88; P < 0.05) for the intermediate CTS5 category. Relative to high-risk postmenopausal patients, the mean observed 10-year distant recurrence risk for the high CTS5 category was 13.83 per cent, which differs significantly from the CTS5 estimation of 10-year distant recurrence risk (20.3 per cent, 95% c.i. 17.2 to 24; P = 0.000). Conclusion The CTS5 can predict late distant recurrence risk in pre- and postmenopausal hormone receptor-positive breast cancer patients. CTS5 overestimates the risk for high-risk patients and thus, its use in these patients warrants caution.

Nipple-sparing mastectomy is an alternative to skin-sparing mastectomy in select patients. Increasing evidence supports its use in the setting of breast cancer, however concerns still exist regarding oncological safety. The aim of this systematic review was to evaluate long-term oncological outcomes of patients who underwent nipple-sparing mastectomy for breast cancer. A systematic review of the literature was performed to evaluate oncological outcomes in patients with breast cancer who underwent nipple-sparing mastectomy. Five major databases (PubMed, Embase, Scopus, Web of Science and Cochrane) were searched. The review included all original articles published in English reporting long-term oncological outcomes. 2334 studies were identified. After applying inclusion and exclusion criteria, 17 retrospective studies involving 7107 patients were included. The indication for nipple-sparing mastectomy was invasive carcinoma in 6069 patients (85.4%) and in situ disease in 1038 (14.6%). Median follow up was 48 months (range 25-94). The weighted mean rates of local recurrence and recurrence involving the nipple-areola complex were 5.4% (0.9-11.9) and 1.3% (0-4.9), respectively. The weighted mean distant failure rate was 4.8% (1.5-23.0). Therapeutic nipple-sparing mastectomy is oncologically safe in select patients with breast cancer.

Administration of chemotherapy before breast surgery has the potential to reduce the risk of distant recurrence by targeting micrometastasis as well as allowing a more minimalistic approach to surgical intervention. We performed a systematic review to determine the optimum timing of surgery post breast cancer neoadjuvant chemotherapy (NACT).The primary outcome was to determine whether the timing of surgery post NACT impacted overall survival (OS) and disease-free survival (DFS). We compared patient outcomes between those who had surgery within 8 weeks of completion of NACT to those that had surgery after 8 weeks. An outcome comparison between4 weeks and 4-8 weeks was also performed. Secondary outcome included complete pathological response (pCR) post NACT. A meta-analysis was performed using the Mantel-Haenszel method.Five studies, including 8794 patients were eligible for inclusion. Patients that had surgery within 8 weeks of completion of NACT had a statistically significant improved OS(OR 0.47, 95% c. i 0.34-0.65) and DFS(OR 0.71 (95% c. i 0.52-0.98, P = 0.04). There were no survival advantages associated with having surgery less than 4 weeks post completion of NACT (OR 0.78, 95% c. i 0.46-1.33, P = 0.37). There was no difference in pCR rate between those that had surgery4 weeks and 4-8 weeks (OR 1.01, 95% c. i 0.80-1.28, P = 0.93).This meta-analysis shows that the optimum timing of surgery post completion of NACT is 4-8 weeks as it is associated with increased OS and DFS.

Results from TAILOR-X suggest that up to 70% of hormone receptor-positive (HR+) node-negative (N0) ESBC patients (pts) may avoid chemotherapy (CT) with RS ≤ 25. We assess clinical and economic impacts of RS testing on treatment using real-world data. From October 2011 to February 2019, a retrospective, cross-sectional observational study was conducted of HR+ N0 ESBC pts who had RS testing in Ireland. Pts were classified low risk (RS ≤ 25) and high risk (RS > 25). Clinical risk was calculated. Data were collected via electronic patient records. Cost data were supplied by the National Healthcare Pricing Regulatory Authority. 963 pts. Mean age is 56 years. Mean tumour size is 1.7 cm. 114 (11.8%), 635 (66%), 211 (22%), 3 (0.2%) pts had G1, G2, G3 and unknown G, respectively. 796 pts (82.8%) low RS, 159 (16.5%) high RS and 8 pts (0.7%) unknown RS. 263 pts (26%) were aged ≤ 50 at diagnosis; 117 (45%) had RS 0–15, 63 (24.5%) 16–20, 39 (15.3%) 21–25 and 40 (15.2%) RS 26–100. 4 pts (1.5%) had unknown RS. Post-RS testing, 602 pts (62.5%) had a change in CT decision; 593 changed to hormone therapy (HT) alone. In total, 262 pts received CT. Of pts receiving CT; 138 (53%) had RS > 25, 124 (47%) had RS ≤ 25. Of pts aged ≤ 50, 153 (58%) had high clinical risk, of whom 28 had RS 16–20. Assay use achieved a 62.5% change in treatment with 73% of pts avoiding CT. This resulted in savings of €4 million in treatment costs. Deducting assay costs, savings of €1.9 million were achieved. Over the 8 years of the study, a 62.5% reduction in CT use was achieved with savings of over €1,900,000.

Background: The use of the 21-gene recurrence score assay (RS) has reduced chemotherapy (CT) administration in patients with hormone receptor (HR)-positive, HER-2 negative, lymph-node negative, early stage breast cancer (ESBC). Invasive lobular carcinoma (ILC) accounts for up to 15% of all breast cancers. This study uses real world data to assess (1) the effect of RS testing on treatment decision making in patients with ILC and (2) the economic benefit of testing in this subgroup. Methods: From October 2011 to February 2019, a retrospective, cross-sectional, observational study was conducted on HR+, HER-2 negative, lymph-node negative, ESBC patients with ILC who had RS testing in Ireland. For the decision impact analysis, a survey of Irish breast medical oncologists presumed that, without RS testing, CT would be recommended to patients with histological grade (G) 2 and 3 tumours and not for G1 tumours. In accordance with TAILOR-x results, patients were classified overall as low risk (RS≤25) and high risk (RS>25) and patients ≤50 years old were low risk (RS 0-15), intermediate risk (RS 16-25), and high risk (RS>25). Data were collected from electronic patient records. Descriptive statistics were used. Cost data were obtained from the National Healthcare Pricing Regulatory Authority. The economic analysis was adjusted for changing treatment and assay costs over the study period. Results: 166 patients with ILC were identified. Mean age was 59 years. Mean tumour size was 2.3cm (range 0.7-5.8). The majority had G2 tumors (n=152, 92%) with a small number of G3 (n=7, 4%) and G1 (n=7,4%). Overall, 153 patients (92.2%) had a low RS (≤25), 12 (7.2%) had high RS (>25), and 1(0.6%) was unknown. All 12 patients with RS>25 had G2 tumours, 6/12 (50%) had tumour size >3cm, 4(33.3%) were PR+ and 8(66.7%) were PR negative. In 29/166 (17.5%) patients, aged ≤50 at diagnosis, RS was ≤15 in 16(55%), 16-20 in 6(21%), 21-25 in 5(17%), >25 in 1(3.5%) and unknown in 1(3.5%). The majority of these patients (27, 93%) had G2 tumours, 1 had G1 and 1 had G3. Post RS testing 124 patients (74.5%) had a change in CT recommendation; all from CT to hormone therapy. In total, only 35 patients (21%) received CT. In this group, RS was 0-15 in 3(9%), RS 16-25 in 19(54%), RS >25 in 12 (34%) and unknown in 1(3%). Eight of 35 patients (23%) were aged ≤50. The most common CT regimen administered was docetaxel plus cyclophosphamide (TC). RS testing achieved a 78% reduction in chemotherapy use. This resulted in savings of €900,000 in treatment costs. With the incorporation of the assay cost, the net savings totalled approximately €400,000. Conclusions: Ireland was the first public health care system to reimburse the 21-gene recurrence score assay in Europe. There is limited evidence demonstrating the benefits of RS in ILC. In our study, the use of the test has resulted in a 78% reduction in chemotherapy use in an Irish ILC patient population and a substantial cost saving (greater than €400,000) to the Irish Healthcare System. Citation Format: Mehala Tharmabala, Lynda McSorley, Fathiya Al Rahbi, Evoy Denis, James G Geraghty, Rothwell Jane, Damian McCartan, Enda McDermott, Maccon M Keane, John Kennedy, Seamus O'Reilly, Steve Millen, John Crown, Lilian Mary Smyth, Catherine Margaret Kelly, Prichard Ruth, Cecily Quinn, Janice M Walshe. An analysis of the clinical and economic impact of the 21-gene recurrence score (RS) in invasive lobular early-stage breast cancer (ESBC) in Ireland [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-23.

Background The significance of exogenous hormone manipulation as part of fertility treatment and its relationship to the development of breast cancer remains uncertain. Several historical reviews have been performed with conflicting results. This study is an updated meta-analysis to determine whether there is a causal relationship between different fertility treatments and breast cancer. Methods The study report is based on the guidelines of PRISMA and Meta-Analysis of Observational Studies in Epidemiology. Studies published within the last 20 years were included to reflect up to date in vitro fertilization (IVF) practice. This study was prospectively registered on PROSPERO on 07/04/2021, registration identification CRD42021247706. The primary outcome of the study was to determine whether there is an increased incidence of breast cancer in women treated with hormonal fertility treatment. The secondary outcomes were to determine whether fertility treatments were individually associated with excess breast-cancer risk. Results Overall, 25 studies, including 617 479 participants, were eligible for inclusion. There was no significant breast-cancer risk association with fertility treatment (compared with general and subfertility reference groups). Summary odds ratio of all included studies was 0.97 (95 per cent c.i. 0.90 to 1.04). Women who received six or more IVF cycles did not have an increased risk of breast cancer. Similarly, there was no excess breast-cancer risk associated with clomiphene, human chorionic gonadotropin, gonadotropin analogues and progesterone when examined individually. Comparably, there was no significant association between fertility treatment and excess breast-cancer risk in patients with more than 10 years’ follow-up. Summary odds ratio was 0.97 (95 per cent c.i. 0.85 to 1.12). Conclusion This meta-analysis did not find a significant association between fertility treatments and excess breast-cancer risk. Women considering IVF should be informed that it does not appear to increase breast-cancer risk.

Background Since the ACOSOG Z0011 trial, rates of axillary node clearance (ANC) for micrometastatic axillary disease have declined among women undergoing breast conservation surgery (BCS). However, for women undergoing mastectomy, it remains unclear whether omission of ANC is a safe and feasible option. Aims Identify current practice relating to management of the axilla in women with early stage, clinically node negative breast cancer, found to have micrometastatic disease on SNB, who undergo mastectomy Methods From 2013 to 2017 patients with clinical T1-T2Nmi breast cancer undergoing upfront surgery were identified from a prospective institutional database. Receipt of adjuvant radiotherapy or subsequent ANC were assessed. Patients who received neoadjuvant chemotherapy or BCS were excluded. Results 47 patients undergoing mastectomy for ESBC had micrometastasis identified on SNB. The majority of tumours had invasive ductal histology. 16/27 women underwent completion ANC (34%). Six patients had further nodal disease identified in the ANC specimen. 2 had >5 nodes positive. During the study period 31 patients (65%) received adjuvant radiotherapy. Of the patients who did not undergo ANC, 21 (67.7%) received adjuvant radiotherapy. Conclusion At this institution the majority of patients requiring mastectomy with micrometastatic disease on SNB do not undergo subsequent ANC (>60%). Although this is a small patient cohort, these data indicate the rate of residual axillary disease is low, and are in keeping with trends in the literature, and may help inform management decisions in this patient group.

Axillary nodal status remains an important determinant of prognosis and of the therapeutic strategy in patients with a newly diagnosed breast cancer. The aim of this study was to assess the false-negative rate of ultrasound (US)-guided fine-needle aspiration cytology (FNAC) in axillary node staging at breast cancer diagnosis. All patients with a newly diagnosed breast cancer who had an indeterminate or suspicious axillary node sampled with an FNAC between 2007 and 2014 were included in the study. FNAC results were compared to the final histopathological results of surgically removed axillary lymph nodes. Patient demographics, tumor, and nodal characteristics were analyzed. Diagnostic accuracy tests were performed using IBM SPSS, version 22. A total of 3515 patients with breast cancer were identified, 675 of whom had ultrasound-guided FNAC of ipsilateral axillary lymph nodes (mean age: 55 years; Range: 26-84). A benign (C2) result was observed in 52% (n = 351) and a malignant (C5) result in 35% (n = 238). C1 was obtained in 11% (n = 76), C3 in 0.6% (n = 4), and C4 in 0.9% (n = 6). Of the 238 patients with a malignant (C5) FNAC, 99.6% had confirmed axillary lymph node metastatic disease on histopathology. Of the 351 patients with benign FNAC (C2), 31% (n = 108) of patients had a positive lymph node on histology. The false-negative rate of preoperative FNAC remains too high (31%) to omit definitive surgical staging of the axilla. The high diagnostic accuracy when a positive FNAC is obtained allows appropriate tailored decisions regarding definitive therapy.

Introduction Recent studies have suggested that sentinel lymph node biopsy (SLNB) can be omitted in newly diagnosed elderly breast cancer (BC) patients as it may not influence decisions regarding further therapeutic intervention. The aim of this study was to assess the impact of SLNB on further surgical intervention as well as adjuvant treatments in patients over the age of 80. Method A retrospective study was performed involving all BC patients over the age of 80 diagnosed between 2008 and 2017 who underwent SLNB as part of their initial surgery. Patient/tumour characteristics and adjuvant treatments were recorded. Result 127 patients underwent SLNB in the study period. The median age was 82 (Range: 80-95). 91/127 (71.6%) had ductal pathology, median tumour grade was 2, and oestrogen receptor positivity was seen in 89% of patients. The median number of sentinel nodes removed was 2 (Range: 1-6). 45 patients (35.4%) had a positive sentinel node (median positive nodes = 1). Of the 45 patients, 11 proceeded to axillary lymph node dissection (ALND) (11/127; 8.6%). The median number of nodes excised during ALND was 14 (Range:7-25) and 6 patients (6/11) had further positive nodes. 9% of patients with a positive node received adjuvant chemotherapy, 87% received adjuvant radiotherapy and 79% received hormonal therapy. Conclusion Although SLNB positivity is still used in the elderly patients, only a few patients ( Take-home message The use of SLNB in elderly patients needs to be considered in node negative patients

The association between immediate breast reconstruction (IBR)-related wound complications and breast cancer recurrence (BCR) remains uncertain. This study aimed to investigate the oncological outcomes in patients with wound complications following mastectomy and IBR. A comprehensive search was undertaken for all studies describing complications in patients with breast cancer following IBR. Studies were included if they reported on complications and investigated their relationship with BCR. A meta-analysis was performed using a random-effects model, with data presented as odds ratios and 95% confidence intervals. A total of 1418 patients from five studies were included in the final analysis. The mean age of patients included was 47.2 years. A total of 382 (26.9%) patients had postoperative complications following a majority of implant-based IBR (929/1418). A total of 158 (11.1%) recurrences, which included 63 locoregional and 106 distant recurrences, was noted at a mean follow-up of 66 months. Although there was an increase in recurrence rates in the complication group (n = 66/382; 17.3% vs. n = 92/1036; 8.9%), there was no significant association between complications and BCR (17.3% vs. 8.9%; P = .18) or mortality (3.6% vs. 2.3%; P = .15). Time to adjuvant therapy was significantly increased in patients with complications (mean difference, 8.69 days; range, 1.18-16.21 days; P = .02; I2 = 0.02). This meta-analysis demonstrated a higher incidence of wound complications following IBR and a statistically significant increased time to adjuvant therapy. However, this did not translate into adverse oncological outcomes in patients with breast cancer undergoing IBR.

Breast fibromatosis is a rare clinical entity, but poses significant diagnostic and therapeutic challenges. In light of recent changes in management practices, the aim was to review our institutional experience of breast fibromatosis and provide a review of current available literature on such management. A search of pathological databases within two tertiary institutions for all patients diagnosed with fibromatosis of the breast over a 10-year period (2007–2016) was performed. Clinicopathological characteristics and modes of treatment were recorded for each patient. Concurrently a comprehensive literature search was performed and studies relating to breast fibromatosis and its management were identified and reviewed. Sixteen patients were identified. Median age at diagnosis was 42 (range 21–70) and all patients were diagnosed with core biopsy. The most useful imaging modality in diagnosis was ultrasonography and magnetic resonance imaging. 13/16 were treated surgically whilst 3/16 were treated using a watch-and-wait approach. 6/13 (46%) required re-excision of margins and 2/13 (15%) had recurrence after surgery. On review of the literature, there is no dedicated guideline in place for the management of breast fibromatosis. Currently a ‘watch and wait’ approach is favoured over surgical intervention due to high levels of recurrence and associated surgical morbidity. All cases should be discussed at a sarcoma multidisciplinary team meeting and tyrosine kinase inhibitors should be considered in advanced cases. Breast fibromatosis is rare but affects young patients. Active surveillance is now favoured over surgical resection due to high recurrence rates and extensive morbidity. Dedicated guidelines are required to ensure best outcomes.

Background Neoadjuvant chemotherapy for breast cancer has the potential to achieve a pathological complete response in up to 40 per cent of patients, converting disease that was initially node-positive to node-negative. This has raised the question of whether sentinel lymph node biopsy could be an alternative to axillary lymph node dissection in these patients. The aim was to undertake a systematic review and meta-analysis of the accuracy and reliability of sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with initial biopsy-proven node-positive breast cancer. Methods A literature search was conducted using PubMed, Ovid MEDLINE, Embase and Web of Science databases up to 30 April 2017. Inclusion criteria for studies were pathological confirmation of initial node-positive disease, and sentinel lymph node biopsy performed after neoadjuvant chemotherapy followed by axillary lymph node dissection. Results A total of 13 studies met the inclusion criteria and were included in the analysis (1921 patients in total). The pooled estimate of identification rate was 90 (95 per cent c.i. 87 to 93) per cent and the false-negative rate was 14 (11 to 17) per cent. In subgroup analysis, the false-negative rate with use of dual mapping was 11 (6 to 15) per cent, compared with 19 (11 to 27) per cent with single mapping. The false-negative rate was 20 (13 to 27) per cent when one node was removed, 12 (5 to 19) per cent with two nodes removed and 4 (0 to 9) per cent with removal of three or more nodes. Conclusion Sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with biopsy-proven node-positive breast cancer is accurate and reliable, but requires careful patient selection and optimal surgical techniques.

Background The optimal timing of (neo)adjuvant trastuzumab initiation with respect to chemotherapy and surgery remains undefined. Methods Retrospective analysis of a large institutional database of HER2-positive patients who received anti-HER2 therapy. We included all Stage I to III patients treated with trastuzumab with a minimum follow up of 3 years. The date of first breast biopsy was recorded as initial diagnosis. Results A total of 506 patients [adjuvant: 386 (76%)-neo-adjuvant: 120 (24%)] were included. The median time-to-first-trastuzumab (TFT) from diagnosis was 12 weeks (range 1.9–122.3). Median follow-up is 73.3 months (range 1.4–176.3). TFT was significantly shorter in the neo-adjuvant than in the adjuvant cohort (median: 4.4 vs. 14 weeks, p 12 weeks. Early concomitant regimens were associated with superior DFS over delayed-concomitant and sequential regimens. Conclusions Initiating trastuzumab more than 12 weeks from diagnosis has a negative impact on clinical outcome. Neo-adjuvant anti-HER2 therapy could be the optimal strategy to treat early stage HER2-positive breast cancer.

Therapeutic mammaplasty (TM) may be an alternative to mastectomy, but few well designed studies have evaluated the success of this approach or compared the short-term outcomes of TM with mastectomy with or without immediate breast reconstruction (IBR). Data from the national iBRA-2 and TeaM studies were combined to compare the safety and short-term outcomes of TM and mastectomy with or without IBR.The subgroup of patients in the TeaM study who underwent TM to avoid mastectomy were identified, and data on demographics, complications, oncology and adjuvant treatment were compared with those of patients undergoing mastectomy with or without IBR in the iBRA-2 study. The primary outcome was the percentage of successful breast-conserving procedures in the TM group. Secondary outcomes included postoperative complications and time to adjuvant therapy.A total of 2916 patients (TM 376; mastectomy 1532; mastectomy and IBR 1008) were included in the analysis. Patients undergoing TM were more likely to be obese and to have undergone bilateral surgery than those having IBR. However, patients undergoing mastectomy with or without IBR were more likely to experience complications than the TM group (TM: 79, 21·0 per cent; mastectomy: 570, 37·2 per cent; mastectomy and IBR: 359, 35·6 per cent; P 0·001). Breast conservation was possible in 87·0 per cent of patients who had TM, and TM did not delay adjuvant treatment.TM may allow high-risk patients who would not be candidates for IBR to avoid mastectomy safely. Further work is needed to explore the comparative patient-reported and cosmetic outcomes of the different approaches, and to establish long-term oncological safety.La mamoplastia terapéutica (therapeutic mammaplasty, TM) puede ser una alternativa a la mastectomía, pero hay pocos estudios bien diseñados que hayan evaluado el éxito de esta estrategia o hayan comparado los resultados a corto plazo de la TM con la mastectomía con o sin (+/-) reconstrucción mamaria inmediata (immediate breast reconstruction, IBR). Para comparar la seguridad y los resultados a corto plazo de la TM y la mastectomía +/- IBR se combinaron los datos de los estudios nacionales iBRA-2 y TeaM. MÉTODOS: En el estudio TeaM se identificó el subgrupo de pacientes al que se realizó una TM para evitar la mastectomía y se compararon los datos demográficos, las complicaciones, los resultados oncológicos y el tratamiento adyuvante con las pacientes sometidas a mastectomía +/- IBR del estudio iBRA-2. La variable principal fue el porcentaje de éxito de la cirugía conservadora de mama en el grupo TM. Las variables secundarias fueron las complicaciones postoperatorias y el intervalo de tiempo hasta el inicio del tratamiento adyuvante.Se incluyeron en el análisis 2.916 pacientes (TM n = 376; mastectomía n = 1.532; IBR n = 1.008). La TM era más frecuente en pacientes obesas o en las sometidas a cirugía bilateral en comparación con las pacientes con IBR. Sin embargo, las pacientes sometidas a una mastectomía +/- IBR tenían más probabilidades de desarrollar complicaciones que las del grupo TM (TM n = 79, 21,0%; mastectomía n = 570, 37,2%; mastectomía y IBR n = 359, 35,6%; P 0,001). La conservación de la mama fue posible en el 87% de las pacientes con TM y el procedimiento no retrasó el inicio del tratamiento adyuvante. CONCLUSIÓN: La TM puede permitir que pacientes de alto riesgo que no serían candidatas a IBR eviten la mastectomía de una forma segura. Se necesitan más trabajos para comparar los resultados percibidos por las pacientes y los estéticos de las diferentes estrategias terapéuticas y establecer la seguridad oncológica a largo plazo.

540 Background: Treatment of hormone receptor positive (HR+) ESBC is evolving. The use of chemotherapy (CT) is declining with use of the 21-gene RS assay. This validated tool predicts the likelihood of adjuvant CT benefit in HR+ ESBC. Results from the TAILOR-x study suggest up to 70% of HR+ node negative ESBC patients (pts) may avoid CT with RS ≤25. Our objectives were to assess the clinical and economic impact of RS testing on treatment decisions using real-world data. Methods: From October 2011 to February 2019, a retrospective, cross-sectional observational study was conducted of HR+ node negative ESBC pts who had RS testing in Ireland. A survey of Irish breast medical oncologists provided the assumption for the decision impact analysis that grade (G) 1 pts would not receive CT pre RS testing and G2/3 pts would receive CT. Using TAILOR-x results, pts were classified low risk (RS ≤ 25) and high risk (RS > 25). Data was collected via electronic patient records. Descriptive statistics were used. Cost data was obtained via the National Healthcare Pricing Regulatory Authority. The economic analysis was adjusted for changing treatment and assay costs over the study period. Results: 963pts were identified. Mean age 56 years. Mean tumour size 1.87cm. 114 (11.8%), 636(66%), 211(22%), 2(0.2%) pts had G1, G2, G3 and unknown G respectively (resp). 797pts (82.8%) had low RS, 159 (16.5%) had high RS, and 7pts(0.7%) unknown RS. 251pts(26%) were aged < 51 at diagnosis. Of these, 45(17.9%), 145(57.8%), 58(23%), 3(1.2) had G1, G2, G3 and unknown G resp. 208pts(82.9%) had RS ≤ 25, 39pts(15.5%) had RS > 25 and 4pts(1.6%) unknown RS. In the RS ≤ 25 group, 111pts(44%) had RS 0-15, 59(23.5%) had RS16-20, and 38(15.1%) had RS21-25. Post RS testing 595pts(61.8%) had a change in CT decision; 586 changed to hormone therapy (HT) alone, and 9 from HT to CT. In total, 227pts(23.5%) received CT, and 3pts(0.3%) declined. Of pts treated with CT; 9(4%) had RS 0-15, 89(39.2%) had RS16-25, 129(56.8%) had RS > 25. The most common CT regimen was docetaxel and cyclophosphamide(TC), administered to 121pts(53%). RS assay use achieved a 69% change in treatment decision among G2/3 pts and a net 61% reduction in CT use. This resulted in savings of over €4 million in treatment costs. Deducting the assay cost, net savings of over one million euro was achieved. Conclusions: Ireland was the first public healthcare system to approve reimbursement for RS testing. Over the 8 year period of the study, a net 61% reduction in CT use in Irish pts with HR+ ESBC was achieved with conservative net savings of over €1,000,000.

Developed countries face significant population ageing in the near future. Within 20 years, the average age will approach 50 years and the largest population cohort will be those over 65 years. The incidence of breast cancer increases with age, with a risk in women of 0.44% by the age of 30, 3.82% by the age of 70 and 10% by the age of 80. Breast cancer is responsible for one out of every three cancer-related deaths. Elderly patients have higher mortality rates and most breast cancer-related deaths are observed in women over 65. There appears to be a trend that elderly patients with breast cancer receive less than the standard treatment compared to younger counterparts and this leads to poorer outcomes. The rationale for treating elderly breast cancer patients more conservatively is that breast cancers in this cohort are more commonly oestrogen receptor (ER) positive which gives the clinician the option to treat with hormonal manipulation alone. In addition, elderly patients present at a later stage compared to younger patients who frequently present with early (stages I and II) breast cancer. This review aims to give an overview of the diagnosis, treatment options and surveillance of breast cancer in elderly women (over 75 years) and to discuss the change in perception of the term 'elderly' and the reasons for undertreatment in the elderly patients.

Several "moderate-risk breast cancer susceptibility genes" have been conclusively identified. Pathogenic mutations in these genes are thought to cause a two to fivefold increased risk of breast cancer. In light of the current development and use of multigene panel testing, the authors wanted to systematically obtain robust estimates of the cancer risk associated with loss-of-function mutations within these genes. An electronic search was conducted to identify studies that sequenced the full coding regions of ATM , CHEK2 , BRIP1 , PALB2 , NBS1 , and RAD50 in a general and gene-targeted approach. Inclusion was restricted to studies that sequenced the germline DNA in both high-risk cases and geographically matched controls. A meta-analysis was then performed on protein-truncating variants (PTVs) identified in the studies for an association with breast cancer risk. A total of 10,209 publications were identified, of which 64 studies comprising a total of 25,418 cases and 52,322 controls in the 6 interrogated genes were eligible under our selection criteria. The pooled odds ratios for PTVs in the susceptibility genes were at least >2.6. Additionally, mutations in these genes have shown geographic and ethnic variation. This comprehensive study emphasizes the fact that caution should be taken when identifying certain genes as moderate susceptibility with the lack of sufficient data, especially with regard to the NBS1 , RAD50 , and BRIP1 genes. Further data from case-control sequencing studies, and especially family studies, are warranted.

The identification of the breast cancer susceptibility genes BRCA1 and BRCA2 enhanced clinicians' ability to select high-risk individuals for aggressive surveillance and prevention, and led to the development of targeted therapies. However, BRCA1/2 mutations account for only 25% of familial breast cancer cases. To systematically identify rare, probably pathogenic variants in familial cases of breast cancer without BRCA1/2 mutations, we developed a list of 312 genes, and performed targeted DNA enrichment coupled to multiplex next-generation sequencing on 104 'BRCAx' patients and 101 geographically matched controls in Ireland. As expected, this strategy allowed us to identify mutations in several well-known high-susceptibility and moderate-susceptibility genes, including ATM (~ 5%), RAD50 (~ 3%), CHEK2 (~ 2%), TP53 (~ 1%), PALB2 (~ 1%), and MRE11A (~ 1%). However, we also identified novel pathogenic variants in 30 other genes, which, when taken together, potentially explain the etiology of the missing heritability in up to 35% of BRCAx patients. These included novel potential pathogenic mutations in MAP3K1, CASP8, RAD51B, ZNF217, CDKN2B-AS1, and ERBB2, including a splice site mutation, which we predict would generate a constitutively active HER2 protein. Taken together, this work extends our understanding of the genetics of familial breast cancer, and supports the need to implement hereditary multigene panel testing to more appropriately orientate clinical management.

An association between interval breast cancers (cancer detected after a normal mammogram and before the next scheduled mammogram) and tumour aggressiveness has been postulated which may reflect their relatively poor overall prognosis. The aim of this study was to evaluate known prognostic features of screen detected breast cancers compared to interval breast cancers.Patients diagnosed with breast cancer between January 2010 and 2013 at a single unit of the National Breast Screening Program (NBSP) in Ireland and those between the ages of 50 and 65 diagnosed at a symptomatic breast clinic were included in the study. Patients who had not had a screening mammogram within the proceeding two years or had a previous history of breast cancer were excluded. Data were retrospectively collected on patient demographics, tumour type, grade, hormone receptor status and stage of disease at presentation.There were 915 patients included in the study, with 92% (n = 844) diagnosed through the NBSP. Ductal carcinoma in-situ accounted for 19% (n = 160) of screen-detected breast cancers but only 2.8% of interval cancers (p 0.05). The most common type of invasive cancer was invasive ductal carcinoma. Tumour grade was significantly higher in interval breast cancers (p 0.05). Interval cancers were identified at a significantly higher stage (Stage 1 versus 2; p 0.001) than screen-detected cancers. Interval breast cancers were less likely to be ER positive (76% versus 81%; p 0.05) and significantly more likely to over-express HER2 (20% vs 10%, p 0.05) than screen-detected cancers.This study highlights the fact that interval cancers appear to have a number of adverse prognostic markers for overall breast cancer survival when compared to women with screen-detected breast cancers. Interval cancers were more likely to be invasive, of a higher grade and stage and with a greater predominance of HER2 and triple negative molecular subtypes. Therefore this heterogeneous group of tumours may be biologically more aggressive and account disproportionately to overall breast cancer mortality.

Breast cancer is the leading cause of cancer deaths in females worldwide occurring in both hereditary and sporadic forms. Women with inherited pathogenic mutations in the BRCA1 or BRCA2 genes have up to an 85% risk of developing breast cancer in their lifetimes. These patients are candidates for risk-reduction measures such as intensive radiological screening, prophylactic surgery or chemoprevention. However, only about 20% of familial breast cancer cases are attributed to mutations in BRCA1 and BRCA2 , while a further 5–10% are attributed to mutations in other rare susceptibility genes such as TP53 , STK11 , PTEN , ATM and CHEK2 . A multitude of genome wide association studies (GWAS) have been conducted confirming low-risk common variants associated with breast cancer in excess of 90 loci, which may contribute to a further 23% of the heritability. We currently find ourselves in "the next generation", with technologies offering deep sequencing at a fraction of the cost. Starting off primarily in a research setting, multi-gene panel testing is now utilized in the clinic to sequence multiple predisposing genes simultaneously (otherwise known as multi-gene panel testing). In this review, we focus on the hereditary breast cancer discoveries, techniques and the challenges we face in this complex disease, especially in the light of the vast amount of data we now have at hand. It has been 20 years since the first breast cancer susceptibility gene has been discovered and there has been substantial progress in unraveling the genetic component of the disease. However, hereditary breast cancer remains a challenging topic subject to common debate.

Aims Women with inherited pathogenic mutations in the BRCA1 or BRCA2 genes have up to an 85% risk of developing breast cancer in their lifetime. However, only about 20% of familial breast cancer is attributed to mutations in BRCA1 and BRCA2, while a further 5–10% are attributed to mutations in other rare susceptibility genes such as TP53, STK11, PTEN, ATM and CHEK2. Despite extensive efforts to explain the missing heritability of this disease, the majority of familial clustering in breast cancer remains largely unexplained. We aim to analyze the pathology of familial cases of which no pathogenic mutation is yet identified. Methods We compared the pathological phenotype of BRCA1/BRCA2 negative familial breast cancer (BRCAx) to BRCA1-positive, BRCA2-positive and sporadic cases without a family history. Age-adjusted analysis is summarized in odd's ratios and confidence intervals for tumor type, grade, lymph node, ER and HER2 status. Results We found non-familial cases to be more likely to be ER positive ( P = 0.041) as compared with BRCAx tumors. More cases of lobular carcinoma were found with BRCAx as compared to BRCA1 tumors ( P = 0.05). After multivariate logistic regression analysis, BRCAx tumors are more likely ER positive ( P = 0.001) and HER2 positive ( P = 0.047) in comparison to BRCA1. Conversely, BRCAx cases are less likely to be ER positive ( P = 0.02) but more likely to be HER2 positive ( P = 0.021) as compared with BRCA2 tumors. Conclusion Our findings suggest that BRCA1, BRCA2 and BRCAx tumors differ in phenotype from non-familial and familial BRCA1-positive and BRCA2-positive tumors. Further studies will need to be performed in this important population in order to develop strategies for early detection and prevention.

The rationalization of cancer services in Ireland saw all women with symptomatic breast problems referred to one of the eight regional cancer centers. A pilot triaging system was introduced in St Vincent’s University Hospital to streamline these services. Women over 35 years who do not meet urgent referral criteria are referred for a mammogram prior to a clinic appointment (“image first”). The aim of this study was to retrospectively determine the recall rates, biopsy rates, and rate of breast cancer identification within this cohort of patients. This was compared to a screening population of patients. Patients triaged into the “image first” group within a one-year period were identified. Results of the initial mammogram, further imaging and subsequent biopsies were recorded. Data relating to number of recalls, number of patients biopsied and number of cancers identified within the Merrion Unit of the National Breastcheck Screening Program was obtained for comparison. One thousand six hundred eighty-eight referrals were triaged as “image first” over this period. 185 (11%) of patients required a biopsy of an identified lesion. Breast cancer was diagnosed in 65 patients (3.9%). During the same study period, of the 42,099 women who were screened for breast cancer, 496 (1.8%) underwent biopsy and 267 (0.63%) were diagnosed with breast cancer. Image first patients, who represent a cohort of “symptomatic” non-urgent women, have a greater rate of breast cancer detection than an asymptomatic screening population. This may have an impact on the appropriate triaging of symptomatic women in a national cancer center.

Introduction Recent years have seen a dramatic shift to more conservative management of the axilla and the presence of a positive sentinel lymph node biopsy does not now automatically mandate an axillary clearance. This is based largely on data from the American College of Surgeons Oncology Group (ACOSOG) Z11 study, which failed to demonstrate a difference in local recurrence or overall survival when an axillary clearance was omitted in a highly selective group of patients with a positive sentinel lymph node. However, the presence of a positive pre-operative ultrasound guided axillary FNAC(Fine Needle Aspiration Cytology) may be representative of a higher burden of axillary disease. Aim Therefore, the aims of this study were firstly to quantify the actual nodal burden in breast cancer patients with a positive pre-operative ultrasound guided axillary FNAC and secondly to identify the number of patients who may have been spared an axillary clearance based on Z11 eligibility criteria. Methods A retrospective review of a prospectively maintained database within a tertiary breast cancer referral centre was performed. All patients with a positive pre-operative axillary FNAC were identified within a five year period (2007 – 2011). Demographic, tumour and biological characteristics and final nodal status were analysed. Eligibility for randomisation according to the Z11 criteria was assessed based on the final pathology and the number of patients who could have been spared an axillary clearance was identified. Results A total of 360 patients were identified with a positive axillary ultrasound guided FNAC. Sixty-three patients had no axillary surgery and three patients had recurrent disease, leaving a total of 294 for analysis. The mean age was 56 years (range 22 – 87). The mean size of the tumour was 31.3mm (range 4mm – 132mm) and the majority were an invasive grade 3 (57%) ductal carcinoma (84%). Luminal A (63%) was the commonest sub-type. The mean number of nodes removed at axillary clearance was 24 (range 7 – 58) while the mean number of positive nodes excised was 6 (range 0 – 47). Of these, the mean number of level I positive nodes was 4, level II was 1 and level III nodes was Overall a total of 78 patients had less than three positive nodes identified in the axilla and potentially may have been eligible for the Z11 study. However, when patients who had a mastectomy, neo-adjuvant chemotherapy were excluded and the presence of extra-capsular nodal involvement was accounted for only 19 (6.4%) patients may have been spared an axillary clearance. Conclusions The presence of nodal positivity on a pre-operative FNAC is associated with a higher burden of axillary disease. Only a minority of these patients would be able to avoid an axillary clearance in the setting of the recent Z11 study. Performing an axillary ultrasound and FNAC of suspicious nodes allows patients to avoid an unnecessary sentinel lymph node biopsy and proceed directly to an axillary clearance. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-18-05.